N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin

1 Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and 2 Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians University, Munich, Germany Submitted 17 July 2008 ; accepted in final form 16 December 2008 Galectin-3 (Gal-3) is secreted by activated macrophages. In hypertension, Gal-3 is a marker for hypertrophic hearts prone to develop heart failure. Gal-3 infused in pericardial sac leads to cardiac inflammation, remodeling, and dysfunction. N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a naturally occurring tetrapeptide, prevents and reverses inflammation and collagen deposition in the heart in hypertension and heart failure postmyocardial infarction. In the present study, we hypothesize that Ac-SDKP prevents Gal-3-induced cardiac inflammation, remodeling, and dysfunction, and these effects are mediated by the transforming growth factor (TGF)-β/Smad3 signaling pathway. Adult male rats were divided into four groups and received the following intrapericardial infusion for 4 wk: 1 ) vehicle (saline, n = 8); 2 ) Ac-SDKP (800 µg·kg –1 ·day –1 , n = 8); 3 ) Gal-3 (12 µg/day, n = 7); and 4 ) Ac-SDKP + Gal-3 ( n = 7). Left ventricular ejection fraction, cardiac output, and transmitral velocity were measured by echocardiography; inflammatory cell infiltration, cardiomyocyte hypertrophy, and collagen deposition in the heart by histological and immunohistochemical staining; and TGF-β expression and Smad3 phosphorylation by Western blot. We found that, in the left ventricle, Gal-3 1 ) enhanced macrophage and mast cell infiltration, increased cardiac interstitial and perivascular fibrosis, and causes cardiac hypertrophy; 2 ) increased TGF-β expression and Smad3 phosphorylation; and 3 ) decreased negative change in pressure over time response to isoproterenol challenge, ratio of early left ventricular filling phase to atrial contraction phase, and left ventricular ejection fraction. Ac-SDKP partially or completely prevented these effects. We conclude that Ac-SDKP prevents Gal-3-induced cardiac inflammation, fibrosis, hypertrophy, and dysfunction, possibly via inhibition of the TGF-β/Smad3 signaling pathway. N -acetyl-seryl-aspartyl-lysyl-proline; cardiac dysfunction; fibrosis; inflammation Address for reprint requests and other correspondence: O. A. Carretero, Division Head, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd., D